AMINO ACID METABOLISM
Synthesis of Urea in Liver The series of reactions that form urea is known as the Urea Cycle or the Krebs-Henseleit Cycle. The urea cycle operates only to eliminate excess nitrogen. One nitrogen of the urea molecule is supplied by free NH3 (obtained from deamination of amino acids) and the other nitrogen by aspartate. The carbon and oxygen of urea are derived from CO2. The first two reactions leading to the synthesis of urea occur in the mitochondria, whereas the remaining cycle enzymes are located in cytosol.
The Krebs- Henseleit Urea Cycle N.B. The reactions of the urea cycle also serve as the pathway for the biosynthesis of arginine
Urea cycle is linked to TCA Fumarate produced by Argininosuccinate lyase reaction is hydrated to malate, which can be transported into the mitochondria and reenter the TCA cycle.
Carbamoyl-P synthase-1 Formation of carbamoyl phosphate by carbamoyl phosphate synthetase-i is the rate-limiting step in the urea cycle. The reaction is driven by cleavage of two molecules of ATP. The enzyme requires N-acetyl glutamate as a positive allosteric activator. N-Acetylglutamate is synthesized from acetyl-coa and glutamate in a reaction for which arginine is an activator.
Fate of Urea Urea diffuses from the liver, and is transported through the blood to the kidneys, where it is filtered and excreted in the urine. A portion of urea diffuses from the blood into the intestine, and is cleaved to CO2 and NH3 by bacterial urease. The produced ammonia is partly lost in the feces, and is partly reabsorbed into blood.
Clinical Correlation Measurement of blood urea nitrogen (BUN) levels provides a sensitive clinical test of kidney function, because filtration and removal of urea are impaired in cases of kidney malfunction. Also, blood ammonia measurements are a sensitive test of liver function.
Hyperammonemia Normal level of serum ammonia: 5 to 50 μmol/l. However, when the liver function is compromised, blood levels can rise above 1000 μmol/l. Such hyperammonemia causes alkalosis & has a direct neurotoxic effect on the CNS. The symptoms of ammonia intoxication include tremors, slurring of speech, somnolence, vomiting, cerebral edema, and blurring of vision. At high concentrations, ammonia can cause coma (hepatic coma) and death.
Types of Hyperammonemia i) Acquired hyperammonemia, which may be a result of an acute process, such as viral hepatitis, ischemia, or hepatotoxins. ii) Hereditary hyperammonemia, which is due to genetic deficiency of any of the five enzymes of the urea cycle mental retardation.
Why & How hyperammonemia causes neurotoxicity?? 1) Ammonia readily traverses the blood brain barrier, and in the brain is converted to glutamate via glutamate dehydrogenase, depleting the brain of -ketoglutarate limits TCA cycle activity and thus decreases energy production. 2) In addition, the increased glutamate glutamine formation, depleting glutamate stores, which are needed in neural tissue because glutamate is a neurotransmitter & a precursor for the synthesis of GABA, another neurotransmitter. 3) Thus, depletion of brain α-kg & Glu affects energy production as well as neurotransmission. 4) As glutamine level rises in the brain, the volume of fluid within glial cells increases cerebral edema.
Treatment of hyperammonemia i) Limiting protein in the diet. ii) Administering compounds that bind covalently to amino acids, producing readily-excreted products. For example, phenylbutyrate, given orally, is converted to phenylacetate, which condenses with glutamine to form phenylacetylglutamine, which is then excreted.
iii) Administration of levulose reduces ammonia through its action of acidifying the colon, which then promotes excretion of ammonia in the feces as NH4+ ions. iv) Oral administration of neomycin reduces the number of intestinal bacteria responsible for NH3 production.
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Select the One Correct Answer Hepatic coma is the result of: a- Deficiency of phenylalanine hydroxylase b- Deficiency of tyrosinase c- Inability of liver to synthesize urea d- Inability of brain to metabolize ammonia Urea is directly produced from the reaction catalyzed by: a- Glutamate dehydrogenase b- Arginase c- Transaminase d- Argininosuccinase
Degradation of Carbon Skeleton of Amino Acids Amino acids can be classified according to the products of degradation of carbon skeleton: Amino acids whose skeletons generate pyruvate or oxaloacetate or other intermediate of TCA cycle, are converted to carbohydrates via gluconeogenesis (glucogenic amino acids). Amino acids whose skeletons generate acetyl-coa or acetoacetyl-coa contribute towards ketogenesis (ketogenic amino acids). Some amino acids give rise to both products upon degradation and so, they are both glucogenic and ketogenic.
Glucogenic & Ketogenic AA Amino acids can not be stored (opposite to fatty acids & glucose) Only ketogenic: Leu & Lys. Both ketogenic and glucogenic: Ile, Thr, Phe, Tyr & Trp. Only glucogenic: other 13 AA.
Gly is a glucogenic amino acid. It is converted to Ser by a reaction involving methylene THFA, and then Ser is metabolized to pyruvate. + H 2 O H 2 O NH 4 O HO CH 2 H C COO NH 3 + H 2 C C NH 3 + COO H 3 C serine aminoacrylate pyruvate Serine Dehydratase C COO
Phe & Tyr are both Glucogenic & Ketogenic Synthesis of Tyr from Phe
Met is converted to S-adenosylmethionine (SAM), the major methyl-group donor in one-carbon metabolism. The formation of SAM is driven by hydrolysis of all 3 phosphate bonds in ATP. The methyl group attached to the tertiary sulfur in SAM is "activated", and can be transferred to acceptor molecules in methylation reactions.
After donation of the methyl group, S-adenosylhomocysteine is hydrolyzed to homocysteine and adenosine. Homocysteine has two fates: if there is a deficiency of Met, homocysteine is remethylated to Met. If Met stores are adequate, homocysteine is converted to cysteine
Elevated plasma level of homocysteine is a cardiovascular risk factor that correlates with the severity of coronary artery disease. Dietary supplementation with folate, vitamin B 12 and vitamin B 6 leads to a reduction in circulating levels of homocysteine.
Synthesis of SAM in the Activated Methyl Cycle
SAM & Biological Methylations